RU2702587C1 - Method for assessing the rate of cerebral blood flow in neuronal activation zones - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to neurology, and can be used for assessment of tissue blood flow parameters in neuronal activation zones. Method for assessing the rate of cerebral blood flow in zones of neuronal activation involves cerebral analysis by non-contrast magnetic resonance perfusion by the method of marked arterial spins (ASL) of pulse modification (pASL), construction of perfusion maps and selection of an area of the cerebral cortex. Test of pASL is carried out with an active cognitive block paradigm consisting of alternating five blocks of rest and five active setting blocks with duration of 10 scans each; wherein the active setting unit is based on the Stroop neuropsychological test: the font color matches or does not match the word value, if the font color matches the value, the patient responds with the word "yes"; obtaining 101 brain scans, where the first scanning is a reference scan; functional and perfusion cards are probed to be combined. That is followed by selecting neuronal activation areas within the cerebral cortex represented by command control network structures and determining their significance, cerebral blood flow velocity values are calculated therein, and if the values are reduced relative to the norm in the state of the active cognitive block paradigm – less than 68.7 ml/100 g/min – the cerebral blood flow is considered to be disturbed.

EFFECT: method provides higher accuracy of analyzing the rate of cerebral blood flow in zones of neuronal activation.

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Description

The invention relates to medicine, in particular to neurology and can be used to assess the parameters of tissue blood flow in areas of neuronal activation.

Today cerebrovascular diseases are one of the most important medical and social problems due to their high percentage in the structure of morbidity, disability and mortality (Cardioneurology. Current status and development prospects. / Z. A. Suslina A.V. Fonyakin, L.A. Geraskina // Collection of articles and theses of the II National Congress “Cardioneurology” / edited by Z. A. Suslina and others, - M., 2012. - P. 7-13). The possibility of the normal functioning of the brain without a full supply of oxygen and other nutrients is impossible. In case of disruption of blood vessels, including at the level of microcapillaries, the blood supply and the influx of necessary nutrients deteriorate, angiopathy of the vessels begins to develop. A decrease in cerebral perfusion is one of the main factors in the development of cerebral ischemia, cognitive impairment, and the formation of stroke. Therefore, of particular interest is the study of cerebral perfusion with an assessment of cerebrovascular reserve (reactivity), neurovascular interaction, the fraction of oxygen extraction in patients with microangiopathy (small vessel disease), as well as the study of perfusion parameters in the base (rest) and active (the fulfillment of one or another paradigm) state of the brain.

Among the methods for assessing the blood supply to the brain, one of the most commonly used in clinical practice is perfusion methods with determination of tissue blood flow parameters. Cerebral perfusion allows you to evaluate brain activity and plays a leading role as an indicator of brain functioning in normal and pathological conditions. Methods of studying tissue blood flow are most often based on assessing changes in the concentration of dye, radiopharmaceutical and contrast agent injected into the vascular bed (Sergeeva A.N. Cerebral hemodynamics in stenotic lesions of the internal carotid arteries (clinical-CT perfusion study). Scientific scientist, Ph.D. in medical sciences, Moscow, 2013, 21 pp.).

An alternative to these methods is non-contrast magnetic resonance perfusion - ASL (labeled arterial backs method), which does not require the administration of a contrast agent, as an endogenous marker is used to create a bolus of “labeled” arterial blood — labeled spins flowing with arterial blood into the brain tissue. As a result, a brain scan gives a series of repeats with a signal averaged over the intensity in each voxel of the image to obtain “control” - basic (without preliminary inversion or saturation of the spins of arterial blood water molecules) and “labeled” images, the contrast of which will be formed in the presence of "Spins. Subtracting the control image from the marked one, we obtain sections with tissue contrast corresponding to the distribution of marked spins in the brain tissue, that is, perfusion images.

A known method for assessing the rate of cerebral blood flow in areas of neuronal activation, including a series of experiments on the validation and standardization of values of the speed of cerebral blood flow (CBF) in comparison with positron emission tomography (PET). Healthy volunteers showed a high correlation of CBF values measured with PET and ASL. The ASL method allows you to evaluate CBF values in any area of the cerebral cortex. As a result of this study, absolute values of the speed of cerebral blood flow at rest were obtained, depending on the selected measurement zone, in the range of 56-71 ml / 100 g / min. (Pronin I.N., Fadeeva L.M., Podoprigora A.E. et al. Spin arterial blood marking (ASL) - a method for visualizing and evaluating cerebral blood flow. Radiation diagnostics and therapy. 2012; 3: 64-78). However, the CBF score is limited in the white matter of the brain due to its low blood flow velocity, leading to reduction and distortion of the ASL signal (van Gelderen P, de Zwart JA and Duyn JH. Pittfalls of MRI measurement of white matter perfusion based on arterial spin labeling Magn. Reson. Med. 2008; 59: 788-795). This source of information is considered as the closest analogue.

The technical result consists in increasing the accuracy of studying the speed of cerebral blood flow in areas of neuronal activation.

The technical result is achieved by assessing the rate of cerebral blood flow in areas of neuronal activation by examining non-contrast magnetic resonance perfusion by the method of labeled arterial spins (ASL), while ASL research is carried out with an active cognitive block paradigm with calculating the speed of cerebral blood flow in areas of the control network in this case, 101 brain scans are obtained, functional and perfusion maps are constructed with their subsequent combination, then zones a are selected activation, in which the indicators of the rate of cerebral blood flow are calculated, and with a decrease in indicators relative to the norm, tissue blood flow is assessed as impaired.

The method is as follows.

To assess the rate of cerebral blood flow in areas of neuronal activation, we used a pulsed version of the labeling of arterial spins - pulsed ASL, in which a radiofrequency pulse at the time of inversion (TI) changes the magnetization in the selected layer of the brain substance through which the feeding arteries pass, resulting in images in which the MR signal is proportional to the rate of cerebral blood flow. To exclude signals from venous structures, when receiving a control image, signals from protons in the region of the brain located above the recording zone are suppressed, which is regulated by the inversion time (TI), providing selection of tissue imaging.

The subject lies calmly in the tomograph with his eyes open while he is being examined in an MRI scan - pulsed ASL, pASL-labeled arterial spins mode with a block design (active paradigm) - a functional ASL consisting of alternating five resting blocks and five active task blocks , lasting 10 scans. A total of 101 brain scans are obtained for each patient, according to which perfusion and functional neuronal activation maps are calculated. The calculation of the rate of cerebral blood flow is carried out in areas of detected neuronal activation. The axial projection scanning parameters in ASL PICORE Q2T mode are as follows: repetition time (TR) 3000 ms, echo time (TE) 11 ms, inversion time (ITversion 700 ms, IT2 1800 ms, Saturation stop time 1600 ms (saturation) ), Flip angle 90 deg (rotation angle), slices 14 (slices), Dist. Factor 25 (distance factor), FoV 192 mm (field of view), Slice thickness 6.0 mm (section thickness), Voxel size 3 × 3 × 6 mm (voxel size), SNR 1.00 (signal to noise ratio), time asqusition (data collection time) 5.14 min, 1 reference slice - М0, 50/50 “control” / “labeled” pairs of pASL images, post labeling delay (delay after labeling spins) - 1.8, ten blocks for the active paradigm. Before the study conduct training exercises. To process perfusion-functional data obtained by the method of labeled arterial spins, an algorithm is used using programs including statistical processing packages, add-ons and applications based on MATLAB13a: SPM5, SPM8 (http://www.fil.ion.ucl.ac.uk / spm), ASL Data Processing Toolbox (https: //cfh.upenn.edvi/~zewang/ASLtbx), ITKSNAP (http://www.itksnap.org). To localize areas of interest across Broadman fields, view and present the data obtained, use xjView 9.0 (Human Neuroimaging Lab, Baylor College of Medicine) based on SPM (Statistical Parametric Mapping). The analysis of functional ASL data in SPM involves the following steps: Realing (alignment), Normalizing (spatial normalization of data relative to the standard MNI coordinate space - Montreal Neurological Institute), Corregistration (correction), Segmentation (segmentation) and Smoothing (smoothing) using a batch file . The perfusion data maps are built in the ASL Data Processing Toolbox program with the possibility of further calculation of CBF digital indicators in the studied areas of the brain. Also, all subjects undergo an MRI scan of the brain in T1 mode gradient echo with a slice thickness of 1 mm in order to obtain anatomical data with the possibility of subsequent reconstruction of images in any planes, co-registration with perfusion and functional data obtained in pulsed spin marking mode of arterial blood pASL - PICOREQ2T for subsequent group analysis. Statistical parametric maps are formed on the basis of peroxel comparison using a common linear model [Friston K.J., Holmes A.R., Worsley K.J. et al. Statistical parametric maps in functional imaging: a general linear approach // Human brain mapping. 1994. V. 2. No. 4. P. 189].

Study design.

We studied 12 healthy volunteers, of which 10 were women, the median age was 58 years, and the 1st and 3rd quartiles [55.5; 59.5] without clinical symptoms and focal changes in the substance of the brain according to MRI. All subjects were right-handed. The subjects signed an informed consent to conduct the survey. The study protocol was approved by the local Ethics Committee of the FSBI NCHS. Neuroimaging examination was carried out on a Siemens MAGNETOM Verio 3 T magnetic resonance imager and included a brain study in T2-spin echo modes in axial projection for screening evaluation of brain matter with parameters: (repetition time (TR - time repetition) 4000 ms, echo time (TE - time echo) 118 ms, slice thickness 5 mm, slice interval 1.5 mm; duration 2 min 2 sec); MPR (3D T1) in a sagittal projection for obtaining isotropic anatomical data with the aim of subsequent superimposition of perfusion-functional data on them and the possibility of reconstructing images in any projections with parameters: (TR 1900 ms, TE 2.5 ms; slice thickness 1.0 mm; inter-slice 1 mm interval; 4 min duration 16 sec), in the functional ASL mode - labeled arterial spins in the axial plane with obtaining 101 repetitions of scanning with alternating 50 control / 50 labeled arterial spins, where the first scan from the ASL stream is the reference (М0), TR 3000 ms, TE 11 ms, slice thickness 6 mm, slice interval 1.5 mm, with simultaneous execution of an active block paradigm consisting of the first reference scan and alternating 5 active and 5 passive blocks of 10 scans each (total 101 brain scans for each patient, according to which perfusion-functional calculation is performed), the scan duration is 6 minutes 20 seconds. In the claimed design of the study, a cognitive active task was chosen based on the Stroop neuropsychological test - when images with the color name are projected onto the patient’s screen. The font color matches or does not match the meaning of the word. Incentives were applied at a speed of 1.5 sec / image, the alternation of images was random. The patient was tasked with reacting to himself with the word "yes" if the font color matched its meaning.

During the statistical analysis of the ASL functional data for each subject, data were obtained on the activation zones in the form of color maps superimposed on the anatomical data, and in digital format indicating the level of statistical significance of the activation zone, its volume and coordinates in the MNI stereotactic space. This analysis was carried out separately for each subject (with a threshold of statistical significance p≤0.05, T> 4.5). Subsequently, xjView 9.0 (Human Neuroimaging Lab, Baylor College of Medicine) based on SPM8 was used to localize areas of interest across Broadman fields, view and present the obtained data. Functional ASL activation zone data was used as a mask for overlay on perfusion cards.

Thus, when studying the pulse modification by the method of labeled arterial spins, the perfusion and functional data of the brain are read at the same time, followed by processing the results in the selected zones of interest, which improves the accuracy of studying the speed of cerebral blood flow in the zones of neuronal activation.

For each subject, obtained as a result of statistical processing, perfusion maps in the labeled arterial spins mode were combined with color maps of neuronal activation zones obtained as a result of processing functional data obtained in the labeled arterial spins mode with active scans of the block paradigm and superimposed on volumetric T1 anatomical reconstruction the brain, indicating the coordinates of the zones in the stereotactic space of the MNI and reliability in digital format, moreover, significant for the assessment We were zone with a threshold reliability p <0.001. In this case, a group analysis was carried out using one-sample student test (one-sample t-test) with a threshold of statistical significance p≤0.001 with determination of tissue perfusion in the brain in areas of neuronal activity and in the same areas without activation (at rest) in normal group.

As a result of the study, in the examined group, when constructing perfusion-functional maps, digital indicators of tissue blood flow were obtained. As a result of processing the functional component of pASL during the execution of the active paradigm, we obtained the zones of neuronal activation of the brain, the coordinates of the peaks of the pASL data zones with a reliability of p <0.001, which are presented in table 1.

The results of the evaluation of neuronal activation during the Stroop test according to pASL data revealed brain activation zones. These included the structures of the control-control networks and the identification of significance (the salience network): dorsolateral prefrontal cortex (DLPFK), premotor cortex (PMK), additional motor cortex (DMK), pre-DMK, lower parietal lobules, anterior cingular cortex (PCC). Identified activation zones control the shift of attention to significant stimuli and decision-making in accordance with the goals and expected results through the interaction of the components of the frontal and lower parietal cortex (Justin L. Vincent, 2008; Steven L. Bressler and Vinod Menon, 2010; MW Cole, Grega Repovs , and Alan Anticevic, 2014).

The neuronal activation zones of healthy volunteers performing a cognitive test obtained by the labeled arterial spins method with a block paradigm superimposed on the anatomical images of the brain are presented in FIG. 1 A, B, (p <0.001). Functional activation zones in the group are norms superimposed on the anatomical images of the brain when performing a cognitive test (A) and based on ASL perfusion data (B).

As a result of the study, when performing an active paradigm with a cognitive task in the examined group, statistically significant zones of neuronal activation are identified, according to the coordinates in the MNI space of which tissue blood flow parameters (cerebral blood flow velocity, CBF) were calculated both in the active state and at rest (without activation).

ASL data were also evaluated using ASLtbx (1Ze Wang, 2012) based on SPM8 to obtain CBF perfusion maps, while the obtained 101 measurements, alternating periods of rest and activation, were divided into the corresponding groups with generation of CBF cards during rest (CBFrest) and during the activation period (CBFactive). In the ITK-SNAP program, previously obtained masks with colored activation zones were superimposed on perfusion maps to accurately calculate the regional CBF in the zones of interest. Thus, for analysis, 2 pairs of CBF cards were obtained for each subject: CBFrest and CBFactive.

As a result of the work in the examined group, the norm in constructing perfusion-functional maps of brain zones obtained by the method of labeled arterial spins of a pulse modification with a block active (cognitive) paradigm according to our processing algorithm, we obtained digital indicators of tissue perfusion - cerebral blood flow velocity (median, 1st , 3rd quartile), in selected areas of the brain, compared with indicators of CBF at rest in the same areas. The highest CBF indicators (see table 2) when performing an active cognitive task are determined in areas according to the corresponding fields of Broadman (PB) - the dorsolateral anterior prefrontal cortex (DLPFK) on the left and right PB 46/9; PCC on the right and left, as well as additional motor cortex (DMK) (PB 6) and premotor cortex (PMK). According to the cognitive concept, the basic function of the prefrontal cortex is the integrated management of mental and motor activity in accordance with internal goals and plans, and in the premotor region of the cortex, a plan and a sequence of movements are formed, which probably determines significant changes in tissue blood flow at the level of DLPFK and DMK / PMK.

CBF - cerebral blood flow velocity; active- perfusion data upon activation (when performing an active paradigm); rest - perfusion data in zones at rest; PB - Broadman field; * - selected reference sites in the temporal lobes; PB21 - zones without activation.

At the same time, the indicators of tissue perfusion - the rate of cerebral blood flow in areas of neuronal activation during the Stroop test at rest in healthy volunteers were (62.3-71.7 ml / 100 g / min), and in the state of active cognitive block paradigm (68, 7-80.3 ml / 100 g / min).

Examples of the method.

Example 1

A healthy volunteer M., male, 50 years old, without focal changes in the substance of the brain according to MRI imaging criteria (Fazekas, 1998). A volunteer conducted an ASL study with an active cognitive block paradigm (based on the Stroop test), a total of 101 brain scans were obtained. ASL. Next, we calculated the speed of cerebral blood flow in the zones of the control control network. We built functional and perfusion cards with their subsequent combination. Then, activation zones were chosen in which cerebral blood flow velocity indices were calculated by the statistical processing described above. For this test subject, indicators were found within normal values (70.5-79.0 ml / 100 g / min) of activation of cognitive zones, including: DLPFK on both sides, PMK, DMK on the right / left with a confidence threshold of p <0.001. In FIG. Figure 2 shows the indicated zones of functional activation of a healthy volunteer superimposed on a 3D-MPR image of the volunteer's brain when performing the Stroop cognitive test based on ASL perfusion data.

Example 2

A healthy volunteer L., a 52-year-old man, without focal changes in the substance of the brain according to MRI imaging criteria (Fazekas, 1998). Using the algorithm for statistical processing of an ASL study with an active block cognitive paradigm for a test subject from the obtained volume of 101 brain scans, cerebral blood flow velocity (CBF) and CBF growth were calculated while performing a cognitive test in selected cognitive areas of the brain (ml of blood / 100 g of tissue / min ), including: DLPFK on both sides, DMK / PMK with a confidence threshold of p <0.001. The data are presented in table 4.

According to the data obtained, it can be seen that the CBF blood flow velocity in the state of the active cognitive block paradigm corresponds to the boundaries of normal values and is (76.2-79.5 ml / 100 g / min). That is, a change in the rate of cerebral blood flow in response to a stimulus in selected areas of the brain that provides cognitive control is clearly traced, which is better seen at the level of the dorsolateral prefrontal cortex (DLPFK) and additional motor cortex (DMK) (PB 6) and premotor cortex (PMC) cerebral hemispheres.

In FIG. Figure 3 shows the functional activation zones based on the ASL perfusion data of a healthy volunteer M. superimposed on a 3D-MPR image of a volunteer’s brain when performing a cognitive test with tissue perfusion counts - cerebral blood flow velocity (CBF) when performing a cognitive test in selected cognitive zones of the head brain (ml of blood / 100 g of tissue / min).

Example 3

Patient R., a woman of 59 years old, with moderate cognitive impairment, with focal changes in the substance of the brain according to MRI imaging criteria (Fazekas, 1998), grade 2 - moderate confluent leukoaraiosis around the lateral ventricles of the brain (see Fig. 2). Using the algorithm of statistical processing of an AbL study with an active block cognitive paradigm for a test subject from the obtained volume of 101 brain scans, cerebral blood flow velocity (CBP) values were calculated while performing a cognitive test in selected cognitive areas of the brain (ml of blood / 100 g of tissue / min), including : DLPFK on both sides, PMK, DMK right / left with a confidence threshold of p <0.001. The obtained blood flow velocity data are reduced in comparison with the normal group (less than 68.7-80.3 ml of blood / 100 g of tissue / min). The data are presented in FIG. 4 and in table 5.

* The coordinates of the peak (center) of activation are indicated in the stereotactic coordinate space of the Montreal Neurological Institute - Montreal Neurological Institute - MNI (x, y, z).

As can be seen from the table, the rate of cerebral blood flow in the selected zones of neuronal activation varies between 51.3-62.8 ml of blood / 100 g of tissue / min, which is lower than the baseline (CBF rest) normal values of 68.7-80.3 ml of blood / 100 g of tissue / min.

In FIG. Figure 5 shows the functional activation zones based on the ASL perfusion data of patient R., 59 years old, superimposed on 3D-MPR images of the patient’s brain when performing a cognitive test with calculation of tissue perfusion parameters - cerebral blood flow velocity (CBF) when performing a cognitive test in selected cognitive areas of the brain (ml of blood / 100 g of tissue / min).

Thus, the ASL method can be used not only to determine perfusion parameters of tissue blood flow, but also as a functional study with obtaining brain maps, with neuronal activation zones, with the possibility of further assessing changes in cerebral blood flow velocity in the brain at rest and during cognitive paradigm.

The advantage of the method of labeled arterial spins is the ability to evaluate cerebrovascular reserve (CVR), a reactivity that can be impaired in various diseases of the brain, including strokes, traumatic brain injury, tumors, entering the main pathogenesis of cerebrovascular tissue disorders pathology. An analysis of the state of reactivity mechanisms is of great practical importance, including the need for prescribing optimal vasoactive therapy. The main objectives of the cerebral circulatory system are to minimize deviations of the circulatory and chemical homeostasis of the brain under various functional conditions, which suggests a complex structural and functional organization of the process of regulating cerebral blood flow.

Compared to functional MRI, in which the degree of neuronal activation is indirectly determined (Functional magnetic resonance imaging of rest: possibilities and future of the method Yu.A. Seliverstov, E.V. Seliverstova, RN Konovalov, M.V. Krotenkova, S .N. Illarioshkin), ASL allows us to characterize the hemodynamic response of the brain to a stimulus in physiological values, and makes it possible to quantify CBF in absolute units (ml of blood / 100 g of tissue / min) in the active and basic state with a fairly accurate localization of the neuron site total activation, which is an absolute advantage of the proposed method.

Claims (1)

A method for assessing the rate of cerebral blood flow in areas of neuronal activation, including carrying out a brain study with pulseless magnetic resonance perfusion (ASL) perfusion method (pASL), constructing perfusion maps and selecting a region of the cerebral cortex, characterized in that the pASL study with an active cognitive block paradigm consisting of alternating five resting blocks and five blocks of an active task lasting 10 scans each; the active task unit is carried out on the basis of the Stroop neuropsychological test: the font color matches or does not match the word value, if the font color matches its value, the patient reacts to himself with the word “yes”; receive 101 brain scans, where the first scan is the reference; build functional and perfusion maps with their subsequent combination, then select the neuronal activation zones in the cerebral cortex, represented by the structures of the control control networks and identify their significance, calculate the values of cerebral blood flow velocity in them and with a decrease in indicators relative to the norm in the state of an active cognitive block paradigm - less than 68.7 ml / 100 g / min - cerebral blood flow is assessed as impaired.

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